Bioidentical hormone replacement therapy (BHRT), also known as bioidentical hormone therapy (BHT) or natural hormone therapy, is the use of hormones that are identical on a molecular level with endogenous hormones in hormone replacement therapy. It may also be combined with blood and saliva testing of hormone levels, and the use of pharmacy compounding to obtain hormones in an effort to reach a targeted level of hormones in the body. A number of claims by some proponents of BHT have not been confirmed through scientific testing. Specific hormones used in BHT include estrone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and estriol.
Custom-compounded BHT is a practice almost wholly restricted to the United States and is a form of alternative medicine. It has been promoted as a panacea for many diseases and for relieving the symptoms of menopause beyond the medical objective of reducing the risk of osteoporosis. There is little evidence to support these incremental claims; the hormones are expected to have the same risks and benefits as comparable approved drugs for which there is evidence based on extensive research and regulation, except for progesterone, which may have an improved safety profile than artificial progestogens, though direct comparisons with progestins have not been made. Risks associated with the less-controlled process of compounding bioidentical hormones are not clearly understood. In addition, the accuracy and efficacy of saliva testing have not been definitively proven, and the long-term effects of using blood testing to reach target levels of hormones have not been researched.
The International Menopause Society, American Congress of Obstetricians and Gynecologists, Society of Obstetricians and Gynaecologists of Canada, The Endocrine Society, the North American Menopause Society (NAMS), United States Food and Drug Administration, American Association of Clinical Endocrinologists, American Medical Association, American Cancer Society, and the Mayo Clinic have released statements that there is a lack of evidence that the benefits and risks of bioidentical hormones differ from well-studied non-bioidentical counterparts; until such evidence is produced the risks should be treated as if they are similar; and that compounded hormone products may have additional risks related to compounding. A major safety concern in compounded BHT is that there is no requirement to include package inserts, despite the potential for serious adverse effects (including life-threatening adverse effects) associated with HRT, which can harm consumers as they are misled into believing that any hormone-related problems and dangers are exclusively related to non-bioidentical hormones, and that compounded BHT is safe and has no side effects. In reality, the risks of bioidentical hormones have not been studied to the extent of non-bioidentical hormones, so the risks are not well-understood. Regulatory bodies require pharmacies to include important safety information with conventional hormone replacement therapy (CHRT) via package inserts.
History Bioidentical hormones were first used for menopausal symptom relief in the 1930s, after Canadian researcher James Collip developed a method to extract an orally active estrogen from the urine of pregnant women and marketed it as the active agent in a product called Emmenin. It was supplanted on the market when its manufacturer, Ayerst (later Wyeth Pharmaceuticals), began producing the more-easily manufactured equine estrogens in 1941 under the brand name Premarin; by 1992, Premarin was the most widely prescribed drug in the United States.
In the 1970s, research and reports indicating risks from synthetic conjugated estrogens began to appear. Investigations determined that the addition of a progestogen to estrogen treatment reduced the risks. As early as 1980, the British Medical Journal (now The BMJ) recommended oral bioidentical progesterone as an option when side effects from synthetic progestogens otherwise mandated discontinuing treatment. In May 1998 the FDA approved Prometrium, an oral bioidentical progesterone product produced by Solvay Pharmaceutical.
Physicians John R. Lee and Jonathan Wright were pioneers in the field of BHT. Lee authored several popular books on BHT and promoted custom-compounded BHT, with the goal of achieving what he called a "natural hormone balance". He based this goal on the clinical testing of saliva to establish where "deficiencies" existed, though agencies such as the FDA and the American Congress of Obstetricians and Gynecologists state that blood and saliva testing is unreliable and biologically meaningless. Lee also believed that progesterone acted as a panacea and general health tonic for many health conditions, basing his claims on anecdotal data rather than peer-reviewed research, which has not been supported by any clinical trials. Wright also authored a popular book on BHT. Compared to previous bioidentical formulas that only used estradiol, he promoted a triple-estrogen formula called Triest, which combined three estrogens found in human females: estriol, estradiol and estrone. It was based on an unpublished study whose conclusions did account for how estrogens are processed and excreted in the body—particularly how the liver processes oral estrogens, converting most of them to estrone. No follow-up was performed by Wright to replicate these observations. Wright may have been the first proponent of BHT to use the term bioidentical—the word he coined to describe unpatentable, plant-derived molecules he believed were identical to human hormones. However, no structural crystallographic evidence has been used to support the idea that these molecules are identical to endogenous human hormones. When the Women's Health Initiative's reports on the unappreciated risks of equine estrogens were released, many prescribers of BHT used Wright's assertions (and his terminology) to proclaim the superiority of bioidentical molecules despite a lack of scientifically supported evidence. Following the publication of a popular book written by Suzanne Somers in 2006, the term bioidentical gained more prominence in popular consciousness as a "poorly understood new adjective" regarding hormone replacement therapy.
Terminology There is no single definition for the term bioidentical hormone replacement therapy; it is generally used to refer to 17β-estradiol, but other uses include plant-based or compounded estrogen products that blend estradiol with estriol and sometimes with estrone. A bioidentical hormone is defined as a molecule identical to a hormone produced by the human body (though not all allegedly bioidentical hormones sold by custom-compounding pharmacies are necessarily molecularly identical to endogenous humans). The FDA considers BHT as currently used by BHT advocates to be a marketing term, not a scientific term, and does not recognize its use. The meaning of plant-derived has also been attached to the term bioidentical, and it may also mean that the hormones are "natural"; throughout the 1990s plant-derived, compounded hormones were referred to as "natural hormone therapy". However, the term natural can be applied to all products where the principal ingredient originates from an animal, plant, or mineral source, and both bioidentical and non-bioidentical hormones can be produced from the same plant sources.
BHT is often used to refer to a set of diagnostic, prescribing, preparation and marketing practices including compounding, saliva testing, and an emphasis on countering the effects of aging rather than relieving the symptoms of menopause. This compounded BHT package has been promoted by Somers, Oprah Winfrey, and other proponents as safer and more effective than CHRT, though there is no evidence to support these claims. Compounded BHT has been marketed on the internet by pharmacies that make unfounded claims for its safety and its effectiveness for a variety of conditions.
There are a variety of FDA-approved products, made using bioidentical estrogens and micronized progesterone, used to treat the symptoms of menopause:
Hormone class Type Brand names Preparations Notes Estrogens Micronized estradiolEstrace and others Pill and vaginal creamVaginal cream for vaginal symptoms only; sourced from plants; estradiol is bioidentical until ingested and converted in the liver to estroneAlora, Climara, Esclim, Estraderm, Vivelle and othersPatchSourced from plantsEstrogelTransdermal gelSourced from plantsEstrasorbTopical creamSourced from plantsEstringVaginal ringFor vaginal symptoms only; sourced from plantsEstradiol acetateFemringVaginal ringEstradiol hemihydrateVagifemVaginal tabletFor vaginal symptoms only Micronized progesterone Micronized progesteronePrometriumPillProchieve 4%Vaginal gel
The term synthetic is also used incorrectly in two ways: to refer to the process used to manufacture all estrogens, including bioidentical estrogens, and to compounds that interact with estrogen receptors similarly to estrogen molecules but are not found in nature. Examples of the latter two include diethylstilbestrol and ethinylestradiol.
Uses
BHT is used to reduce the symptoms of menopause. It is also promoted by some practitioners for anti-aging purposes providing benefits beyond menopausal symptom relief, such as improving quality of life, though there is little evidence to support these claims.
Components and compounding Compounded preparations of bioidentical hormones usually include estriol, estrone, estradiol, testosterone, progesterone, and sometimes dehydroepiandrosterone (DHEA), either individually or combined. They are promoted as natural, safer and (in some cases) more efficacious than CHT; however, there are no scientific studies to support claims of superiority of BHT over CHRT. Estimates from sales of bulk hormones for compounding suggest that more than one million women may be using compounded BHT in the United States. Bioidentical hormones are expected to have the same risks as conventional hormones made with the same categories of hormones.
Estrogens In premenopausal women the majority of estrogen produced by the body is estradiol (produced primarily in the ovaries), while in postmenopausal women estrone (produced in fat cells) is the type of primary estrogen present; however, the body is able to convert one type of estrogen into another to a certain extent. Because of the limited research into potency, delivery methods, and conversion of the various estrogens, a valid scientific understanding of compounded estrogen products has not been achieved. Synthetic estradiol, taken orally, decomposes when absorbed in the gastrointestinal tract and delivers bioidentical estradiol to the bloodstream.
The hormone estriol, produced during pregnancy, is frequently compounded into bioidentical preparations in the United States. While some think it to be a weaker estrogen, with a more limited period of effectiveness than estradiol, it has been demonstrated to be a stronger estrogen in certain ways. Though initial research in the 1970s suggested possible use, follow-up studies have failed to confirm this potential. (free subscription required) Estriol is not found in any FDA-approved drug, and its safety and effectiveness as a hormone supplement is unknown.